Journal Club

Highlighting recently published papers selected by Academy members

Serotonin alters body’s insulin response in pregnancy

While most people have to worry about eating just enough to keep their own body functioning, a pregnant woman has an extra job: keeping nutrients flowing toward her baby. In a new PNAS Early Edition paper, researchers have discovered one way that the pregnant body adapts to ensure that a fetus gets appropriate nutrition. An increase in the hormone serotonin, they found, changes the way cells in the pancreas function. The finding not only explains normal physiology, but could shed light on why some women are at greater risk of developing diabetes during pregnancy.

“During pregnancy, the mother must maintain concentrations of nutrients in her blood stream higher than in the child’s to ensure a constant flow of nutrients to the fetus,” explains Michael German of the University of California, San Francisco, a senior author on the new paper. “If nothing changed in the mother’s metabolism, her glucose levels could frequently drop too low to feed the child.”

In a non-pregnant person, when glucose levels rise, pancreatic beta cells respond by producing and releasing insulin. Insulin, in turn, stimulate tissues in the body to take up the circulating glucose, and blood glucose levels drop off. But in a pregnant woman, glucose must remain high—even hours after a meal—so that the mother’s glucose never falls below the levels in the fetus. To ensure this, a pregnant woman becomes less responsive to surges of insulin.

But simultaneously, the woman’s own body will malfunction if glucose gets too high immediately after eating, as happens to diabetes patients. So at the same time the body becomes more resistant to insulin, the pancreas must be reprogrammed to produce more insulin than usual in response to a meal.

“Beta cells need to make some changes so that all this happens,” says German. In 2010, German and his colleagues discovered that the hormone serotonin—which increases by nearly a thousand fold in pregnancy—was responsible for causing an increase in the number of insulin-producing beta cells during pregnancy. They knew, however, that not only did the number of beta cells increase in pregnant women, but also each beta cell began secreting more insulin. They wondered whether serotonin also caused this second change.

In their latest work, using mice, German, co-senior author Shinya Nagamatsu, lead authors Mica Ohara-Imaizumi and Hail Kimand a team of researchers from the US, Japan and Korea probed the effect of serotonin on insulin secretion during pregnancy. They discovered that serotonin makes beta cells “leaky” to positively charged ions.  The leakiness changes the charge on the beta-cell surface, and decreases the threshold for insulin secretion—when glucose levels rise even slightly, insulin secretion is spurred. When serotonin receptors were removed from beta cells, pregnant mice no longer had increased insulin secretion, their beta-cells acted like those found in non-pregnant mice, and they developed gestational diabetes.

In most cases, the changes in the mother’s metabolism during pregnancy are a good thing—they ensure a balance of health for both mother and fetus. But in some women, the changes can spiral out of control into full-blown gestational diabetes. The new findings could help explain that risk.

“I strongly suspect that genetic variants in this system are what put some women at risk for gestational diabetes,” says German. If pregnancy causes insulin resistance, for example, but not a serotonin-induced increase in insulin production by beta cells, then glucose levels will rise too high after meals and cause diabetes.

Further work on the signaling pathways that are involved—especially in humans—can shed light on what imbalance in the pathway may cause gestational diabetes.

“More broadly, people with type 1 and type 2 diabetes have a deficiency of beta cells,” adds German. “So learning how to boost production or activity of beta cells can potentially help us develop new ways to treat all diabetes.

Categories: Cell Biology
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